tbuckley/cabot-search huggingface dataset:
Fixed-duration venetoclax plus obinutuzumab improves quality of life and geriatric impairments in FCR-unfit patients with CLL
Authors: Lina van der Straten, Claudia A. M. Stege, Sabina Kersting, Kazem Nasserinejad, Julie Dubois, Johan A. Dobber, Clemens H. M. Mellink, Anne-Marie F. van der Kevie-Kersemaekers, Ludo M. Evers, Fransien de Boer, Harry R. Koene, John Schreurs, Marjolein van der Klift, Gerjo A. Velders, Ellen van der Spek, Hanneke M. van der Straaten, Mels Hoogendoorn, Michel van Gelder, Eduardus F. M. Posthuma, Hein P. J. Visser, Ilse Houtenbos, Cecile A. M. Idink, Djamila E. Issa, Ellen C. Dompeling, Henk C. T. van Zaanen, J. Hendrik Veelken, Henriette Levenga, Lidwine W. Tick, Wim E. Terpstra, Sanne H. Tonino, Peter E. Westerweel, Anton W. Langerak, Arnon P. Kater, Mark-David Levin
Journal: Blood (2023)
A virtual memory CD8+ T cell-originated subset causes alopecia areata through innate-like cytotoxicity
Authors: Joon Seok, Sung-Dong Cho, Jeongsoo Lee, Yunseo Choi, Su-Young Kim, Sung-Min Lee, Sang-Hoon Kim, Seongju Jeong, Minwoo Jeon, Hoyoung Lee, A. Reum Kim, Baekgyu Choi, Sang-Jun Ha, Inkyung Jung, Ki-Jun Yoon, Jong-Eun Park, Jong Hoon Kim, Beom Joon Kim, Eui-Cheol Shin, Su-Hyung Park
Journal: Nature Immunology (2023)
Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome
Authors: Alessandro Bitto, Anthony S. Grillo, Takashi K. Ito, Ian B. Stanaway, Bao M. G. Nguyen, Kejun Ying, Herman Tung, Kaleb Smith, Ngoc Tran, Gunnar Velikanje, Silvan R. Urfer, Jessica M. Snyder, Jacob Barton, Ayush Sharma, Ernst-Bernhard Kayser, Lu Wang, Daniel L. Smith, J. Will Thompson, Laura DuBois, William DePaolo, Matt Kaeberlein
Journal: Nature Metabolism (2023)
Globally reduced N6-methyladenosine (m6A) in C9ORF72-ALS/FTD dysregulates RNA metabolism and contributes to neurodegeneration
Authors: Yini Li, Xiaoyang Dou, Jun Liu, Yu Xiao, Zhe Zhang, Lindsey Hayes, Rong Wu, Xiujuan Fu, Yingzhi Ye, Bing Yang, Lyle W. Ostrow, Chuan He, Shuying Sun
Journal: Nature Neuroscience (2023)
RF02 Using functional genomic techniques to help us understand the <i>TYK2</i> pathway in psoriasis
Authors: Sarah Elyoussfi, Shraddha Rane, Stephen Eyre, Richard Warren
Journal: British Journal of Dermatology (2023)

Abstract Genetic screens have identified around 126 genetic signals associated with psoriasis through genome-wide association studies (GWAS) and rare variant analyses (Tsoi LC, Stuart PE, Tian C et al. Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants. Nat Commun 2017; 8:15382). The aim of this study was to use genome-editing techniques to investigate and validate the effect of a psoriasis-associated genetic signal on the expression of TYK2. GWAS have linked TYK2 to psoriasis susceptibility through the association of a protein-changing, exonic variant where TYK2 impairment confers protection against the development of psoriasis and other autoimmune diseases. The vast majority of disease risk-associated variants are found outside gene-coding regions. Functional experimental techniques may help characterize the effect of these variants on gene expression. The development of genome editing technology, clustered regularly interspaced short-palindromic repeat-Cas9 (CRISPR-Cas9), has made it possible to edit cell genomes. We used CRISPR-Cas9 to validate functionally the psoriasis-associated single nucleotide polymorphism (SNP) rs892085 on TYK2 expression in immortal T-cell lines. In-house data from our centre revealed the presence of long-range physical interactions between rs892085 and TYK2. We are the first to investigate functionally this signal and characterize this physical connection. We used CRISPR-Cas9 systems to both activate and inhibit the region around rs892085 and then measured the consequence of this through informative functional readouts using quantitative reverse transcription polymerase chain reaction. This revealed consistent alteration of TYK2 expression upon inhibition and activation of rs892085. This supports previous observations, where this regulatory region harbouring GWAS-implicated variation operates through direct long-distance contact. Previously, the closest or most biologically relevant gene was often assigned to a GWAS variant. We have shown that this is unreliable, with DNA regions looping over large distances to control genes. This work provides the first functional validation of the psoriasis-associated SNP rs892085. TYK2 is a recognized drug target with one therapy, deucravacitinib, approved by the US Food and Drug Administration. Drugs entering the clinical development stage that have used human genetic data to select drug targets may be more likely to succeed. This work demonstrates the potential complexity of how risk alleles may work to dysregulate TYK2 signalling in disease, with both gene function and expression increasing the risk of disease. Ultimately, genetic risk scores, incorporating functional evidence from studies like this, may be generated to predict how patients with different genetically perturbed biology pathways may respond to therapy.
DP03 (P23) Primary penile melanoma and penile lichen sclerosus
Authors: Kate Dear, George Kravvas, Sharmaine Sim, Mariel James, Richard Watchorn, Aiman Haider, Peter Ellery, Alex Freeman, Hussain Alnajjar, Asif Muneer, Chris Bunker
Journal: British Journal of Dermatology (2023)

Abstract The association between squamous cell malignancies and genital lichen sclerosus (GLSc) is well established. There is an increasing literature regarding the relationship of GLSc with genital malignant melanoma (MM). While there have been several reported cases of vulvar melanoma associated with lichen sclerosus (LSc), there have been fewer cases published with regard to male genital (M)GLSc and penile (Pe)MM. The aims of this study were to explore the relationship between PeMM and MGLSc by reviewing all cases managed by our multidisciplinary service over a period of 11 years. All patients known to our tertiary urology and male genital dermatology service with a diagnosis of penile MM and where histology was available for review were identified over an 11-year period (2011–2022). Two independent dermatologists reviewed the clinical records and photographs where available. Two independent mutually blinded histopathologists reviewed the histology and recorded features of GLSc where present. In cases of discordance between histopathologists, a third independent histopathologist reviewed the cases. Eleven patients were identified for inclusion in the study. Overall, GLSc was present on histopathology in nine of 11 cases (82%). Findings were concordantly positive in five cases and concordantly negative in one case. In cases of discordant findings (n = 5), the third histopathologist determined GLSc to be present in four cases and absent in one case. Clinical photographs were available for three cases, and clinical features of GLSc were seen in all of them; they also all had positive histopathological findings. Clinical notes, including electronic notes and letters, were available for review in eight cases. Symptoms in keeping with GLSc were mentioned in only one case, and signs suggestive of GLSc were documented in three cases. Penile MM is a rare entity accounting for 0.7% of penile cancer and 0.1% of MM cases. Like other malignancies, MM is a multifactorial disease caused by a combination of environmental factors and altered host responses contributing to an alteration of regulatory processes. Although ultraviolet exposure is important in the pathogenesis of extragenital MM, this cannot be a factor for genital disease. However, specific risk factors for genital MM have not yet been elucidated. To our knowledge, there have only been three previously documented cases (all from our group) of PeMM coexisting with GLSc. In this present study, finding of GLSc in nine of 11 men with PeMM is suggestive of a causative relationship. We postulate that this is related to chronic melanocytic distress created by chronic inflammation secondary to LSc.
PD01 First UK report of pregnancy and childbirth in X-linked erythropoietic protoporphyria
Authors: Danja Schulenburg-Brand, James Powell, Pushplata Srivastava, Rebecca Swingler, Russell Peek
Journal: British Journal of Dermatology (2023)

Abstract X-linked erythropoietic protoporphyria (XLEPP), an exceptionally rare form of cutaneous porphyria, is characterized by significant acute painful photosensitivity and a risk of both reduced bone mineral density and protoporphyric hepatopathy that may progress to liver failure. Diagnosis requires demonstration of significantly elevated red cell total porphyrins consisting of both zinc and free protoporphyrin analysed on venous whole blood. As the condition is X-linked, any offspring of an affected woman has a 50% chance of inheriting the disease-causing ALAS2 gain-of-function mutation. There are no reported cases of pregnancy in XLEPP in the literature, and no published experience of managing newborn infants that may have inherited XLEPP who develop neonatal jaundice, which requires treatment with phototherapy. Here we describe the clinical course of a 29-year-old woman with XLEPP (part of a four-generation XLEPP family) and idiopathic thrombocytopenia during pregnancy—the first documented case in the UK, to our knowledge. A multiprofessional team considered the potential risks posed by XLEPP and idiopathic thrombocytopenia for the pregnancy, birth and newborn. Haematological and biochemical indices were monitored throughout the pregnancy. The mother experienced increased photosensitivity and worsening idiopathic thrombocytopenia during the pregnancy, the majority of which occurred over summer. Idiopathic thrombocytopenia did not respond to treatment with steroids and immunoglobulin, necessitating a general anaesthetic for the planned caesarean section. A male infant was born in good condition at term. Maternal blood loss was only just above average. The baby remained well in the immediate postnatal period. Although the baby did not require treatment for jaundice, management planned in advance included minimizing factors predisposing to jaundice, including optimal timing of cord clamping and early feed support, the urgent analysis of cord blood erythrocyte porphyrins within 24 h, using a light-emitting diode phototherapy device with narrow spectrum emission between 450 and 470 nm and minimal emission at 400 nm, monitoring the baby closely for signs of distress and skin changes, and considering adjustment of the phototherapy thresholds or using alternative treatments should jaundice occur. Cord blood erythrocyte total porphyrin results suggested the baby had inherited XLEPP and would be photosensitive. This was later confirmed by mutation analysis.
CPC01 A puzzling panniculitis
Authors: Orla McFeely, Tomas Carroll, Anna Wolinksa, Brian Pierce, Kevin Molloy, Noel G. McElvaney, Anne-Marie Tobin, Caitriona Hackett
Journal: British Journal of Dermatology (2023)

Abstract A 51-year-old White woman was seen by dermatology services for a 3-day history of a painful subcutaneous nodule affecting her right distal calf, which was on a background of recurrent erythema nodosum diagnosed in childhood and an admission 6 months prior secondary to neutrophilic panniculitis affecting the right groin. The patient had sustained a traumatic injury to the leg following a fall. She was treated with oral antibiotics for a presumed infected haematoma. As her pain increased, she presented to the emergency department 3 weeks after the fall. On examination, a tender erythematous subcutaneous lesion with central sloughing was noted. She was tachycardic and hypotensive on presentation. Her C-reactive protein was elevated (172 mg L−1), and leucocytosis (15 × 109 cells L−1), with associated neutrophilia and anaemia (9.0 g dL−1), was noted on complete blood count review. Two days later, despite treatment with intravenous (IV) benzylpenicillin, flucloxacillin, clindamycin and topical clobetasol propionate, the lesion enlarged rapidly. Dermatology was consulted. Viral screens, including HIV, herpes simplex virus, Epstein–Barr virus, cytomegalovirus, and hepatitis B and C, were all negative. Serum protein electrophoresis and serum angiotensin-converting enzyme were within normal limits. Her α-1 antitrypsin level was elevated (3.16 g L−1; reference interval 1.1–2.1 g L−1). Her admission was complicated by sepsis, which required escalation of IV antibiotics to meropenem, vancomycin and clindamycin. Punch biopsy revealed epidermal necrosis and ulceration with extensive neutrophilic dermatosis and dermal abscess formation. The inflammation was seen to extend into the subcutis. Findings were reported as consistent with neutrophilic panniculitis. Colchicine was commenced based on ongoing sepsis and anaemia secondary to acute-on-chronic inflammation. Over 2 weeks, the lesion rapidly enlarged, prompting the introduction of oral corticosteroids (0.5 mg kg−1). Adalimumab and doxycycline were further introduced to reduce steroid requirements. Outpatient echocardiogram and colonoscopy revealed no pathology. Reduced levels of α-1 antitrypsin were noted on two occasions (0.89 g L−1 and 0.91 g L−1), coinciding with normal inflammatory markers following her acute illness. To date, no α-1 antitrypsin genetic abnormality has been detected. Panniculitis can be a rare and life-threatening manifestation of α-1 antitrypsin deficiency. Patients presenting with systemic inflammatory response syndrome and panniculitis have a reportedly high mortality risk. No hepatic or respiratory manifestation of α-1 antitrypsin deficiency was seen in this case, highlighting the importance of considering α-1 antitrypsin deficiency in the assessment of panniculitis and rechecking α-1 antitrypsin in this context as it is an acute-phase reactant.
PA30 The modifying effect of maternal body mass index on the influence of maternal vitamin D supplementation on offspring risk of atopic eczema
Authors: Sarah El-Heis, Stefania D’Angelo, Elizabeth Curtis, Eugene Healy, Rebecca Moon, Sarah Crozier, Hazel Inskip, Cyrus Cooper, Nicholas Harvey, Keith Godfrey
Journal: British Journal of Dermatology (2023)

Abstract We recently published evidence from a randomized controlled trial of the protective effect of antenatal cholecalciferol supplementation on the risk of infantile atopic eczema in infants that were breastfed for &amp;gt; 1 month. Reports that cholecalciferol supplementation has a smaller effect on circulating 25-hydroxyvitamin D levels in individuals with a higher body mass index (BMI) led us to examine whether maternal BMI modifies the effect of vitamin D supplementation on offspring atopic eczema in the first 4 years of life. In the Maternal Vitamin D Osteoporosis Study, which was a double-blind, randomized, placebo-controlled trial, mothers were supplemented (from 14 weeks’ gestation until delivery) with cholecalciferol 1000 IU daily or matched placebo. Maternal characteristics, including BMI, were recorded from pre-pregnancy, and offspring atopic eczema was ascertained based on the UK Working Party Criteria for the Definition of Atopic Dermatitis at the age of 12 (n = 636), 24 (n = 611) and 48 (n = 450) months. Mothers and offspring characteristics did not differ between the intervention and placebo groups except for longer breastfeeding duration in the intervention group. Maternal pre-pregnancy BMI was found to modify the effect of intervention on offspring eczema, so associations between maternal cholecalciferol supplementation and offspring eczema were stratified by categories of BMI (&amp;lt; 25, 25–30 and &amp;gt; 30 kg m−2), with findings expressed as odds ratios (ORs). Models were adjusted for breastfeeding duration, and infant sex as sensitivity analysis showed that the intervention had an impact on male infants that were breastfed. As reported previously, the offspring of mothers who received 1000 IU cholecalciferol had lower ORs of atopic eczema at 12 months of age [OR 0.57, 95% confidence interval (CI) 0.33–0.98]; the intervention did not affect the risk of atopic eczema in offspring at 24 and 48 months. Stratified analysis demonstrated reduced odds of atopic eczema at 12 months of age in the intervention group in infants whose mothers had a BMI &amp;lt; 25 kg m−2 (OR 0.28, 95% CI 0.09–0.92) and 25–30 kg m−2 (OR 0.20, 95% CI 0.04–1.06) but not for those with a maternal BMI &amp;gt; 30 kg m−2. The risk of atopic eczema at 24 and 48 months of age in offspring in the intervention group was not modified by maternal baseline BMI, and interaction terms between intervention and BMI were not statistically significant (P &amp;gt; 0.2). These RCT findings support evidence of an attenuated effect of cholecalciferol supplementation in mothers with a higher BMI and point toward potential preventative strategies for offspring eczema where maternal cholecalciferol supplementation can be considered and doses adjusted for BMI.
PA16 Gynaecomastia associated with isotretinoin
Authors: Peter Phillips, Carolyn Aplin
Journal: British Journal of Dermatology (2023)

Abstract Isotretinoin routinely causes mucocutaneous side-effects, such as cheilitis. Endocrine side-effects are not well documented, although reduced libido has been recognized recently. A 19-year-old male (weighing 60 kg and with a body mass index of 20.4 kg m−2) with no previous medical history developed unilateral left-sided gynaecomastia while taking oral isotretinoin for acne vulgaris (daily dose 20 mg for 1 month, 30 mg for 1 month, then 40 mg). He was taking no other medication or supplements, had never taken anabolic steroids and exercised daily. After 3 months of treatment, he noticed a firm, tender, left-sided subareolar mass, enlarging to 4.5-cm diameter, causing the areola to protrude approximately 5 mm above the level of the contralateral areola. Serum testosterone was 35.9 nmol L−1 (reference interval 8.7–29); a-fetoprotein and human chorionic gonadotropin were normal. Isotretinoin was discontinued, and the breast tissue returned to normal within 2 months, with no recurrence after 3 years of follow-up. Gynaecomastia in young adult males is uncommon, usually bilateral and is typically idiopathic in origin. Potential causes include hypogonadism and medications such as oestrogens, cimetidine, methyldopa, ketoconazole, spironolactone and tricyclic antidepressants. Obesity may lead to a similar appearance (pseudogynaecomastia). Isotretinoin has recently been linked to sexual dysfunction in both sexes, but a link is not proven: symptoms may have started after discontinuing isotretinoin and be long-lasting. Erectile dysfunction, loss of libido, anorgasmia and genital anaesthesia are reported; a minority of male patients have reduced testosterone. Gynaecomastia appears to be a very rare complication of isotretinoin use; only four previous cases have been reported in the literature. It is not listed as a potential side-effect in the Summary of Product Characteristics (SPC) leaflets for generic forms of isotretinoin, only being mentioned in the Roaccutane® SPC. The Medicines and Health products Regulatory Authority, in its updated online information leaflet (March 2022), lists gynaecomastia as a potential side-effect. The British National Formulary’s listing and the British Association of Dermatologists’ isotretinoin patient information leaflet do not mention gynaecomastia; however, reduced libido is stated. The European Medicines Agency and the National Health Service’s isotretinoin information webpage mention no endocrine side-effects. Cessation of isotretinoin was associated with resolution of the gynaecomastia; hence, we believe that it was responsible for it, although the mechanism of induction is unclear. An androgen–oestrogen imbalance has been suggested, leading to relative androgen deficiency. However, our patient had a high level of endogenous androgen, thought to be due to a high muscle mass, and entirely normal sexual function. Although uncommon, we would like to alert colleagues to the possibility of gynaecomastia resulting from isotretinoin treatment.
CPC07 Lupus comedonicus: a not so common entity
Authors: Sophie Diong, Bairbre Wynne, Niamh Leonard
Journal: British Journal of Dermatology (2023)

Abstract Lupus comedonicus (LC) is an exceedingly rare variant of chronic cutaneous lupus erythematosus (CCLE), with only 13 reported cases in the literature to date. While its aetiology remains unknown, hallmarks include the presence of comedones on erythematous plaques, particularly in seborrhoeic areas. We report a case of LC involving the scalp, concha bowl and upper back. A 53-year-old female smoker with a 20-pack-year history and previous unprovoked pulmonary embolism presented to dermatology with a 2-year history of alopecia and rash affecting her face and upper back. She was initially reviewed by oral medicine for ulcers, where erythematous buccal mucosal plaques with white striations were seen. The initial biopsy showed a patchy lichenoid inflammatory infiltrate, raising suspicions for lichen planus; however, repeat biopsy highlighted perivascular inflammation and keratin plugging suggestive of lupus. Full skin examination revealed patchy scarring alopecia with perifollicular scale and erythema. Erythematous infiltrated plaques were seen on the face with similar more indurated lesions on the upper back associated with open comedones. The eponymous Shuster sign was observed in the left conchal bowl, with associated follicular occlusion. Laboratory studies all returned within normal limits, including antinuclear antibody titres and complement levels. Differential diagnosis included lupus erythematosus tumidus, discoid lupus erythematosus and LC. Lesional biopsies taken from her back confirmed LC, highlighting lichenoid inflammation involving follicles and interfollicular skin, with superficial and deep perivascular infiltrate. We commenced oral hydroxychloroquine at 200 mg once daily for management, with topical mometasone furoate 0.1% to be used while awaiting its full effect. Smoking cessation has also been advised given the potentially antagonistic effect of smoking with lupus and hydroxychloroquine. Hypotheses of the pathogenesis of LC include the effect of sun exposure. Ultraviolet radiation is known to not only enhance the activity of CCLE but may also contribute to the formation of comedones. Actinic damage alters collagen of normal skin, promoting sebum retention and follicular plugging. Given its infrequency, LC could be mistaken for benign conditions, including acne vulgaris, naevus comedonicus and Favre–Racouchot disease. It is plausible that the small case numbers are due to current underdiagnoses. It is important for dermatologists to be aware of and accurately diagnose LC. Apart from its potentially destructive, scarring complications, especially in untreated and misdiagnosed cases, it is associated with systemic lupus in 30% of cases. Delay in diagnosis and therapeutic management can be associated with significant potential morbidity and even mortality.